Peter Chiarelli, MD, an assistant professor of clinical neurological surgery at the Keck School of Medicine of USC, reviews multidisciplinary evaluations for diffuse intrinsic pontine glioma, with a focus on neurosurgical perspectives. Historical and current management strategies are also discussed.
Yeah. Hi. My name is Peter Chiarelli. I'm a pediatric neurosurgeon at U. S. C and C h l A. Children's Hospital, Los Angeles. Uh, this discussion is on pediatric diffuse brain stem tumors. Pediatric brain stem tumors arise in many forms. For example, the images you're seeing here represented diffuse tumor. However, these tumors can also appear very circumscribed, and furthermore, they could grow away from the back. The dorsal side of the brain stem, as in this door, selects acidic tumor. Seen here. Not all brain stem tumors behave in a similar way. Understanding the difference between these types is essential for providing an appropriate prognosis and inappropriate treatment plan, including surgical treatment when necessary. First off, let's talk about some demographics and certain classifications schemes for brain stem tumors in pediatric population from the most current data from the United States, brain stem tumors represent 10.9% of all new central nervous system NIA plasm in kids age 0 to 19. Just by comparison, these tumors of the brain stem make up 1.5% of brain stem brain tumor. Central nervous system tumors overall in adults, they're approximately 500 new cases per year. Based on the most updated statistics and in pediatrics, and a new diagnosis of brain stem tumor is most common between the ages 5 to 9. Masses in the brainstem display a substantial degree of histological, heterogeneity and really diffuse tumors are the most lethal pediatric high grade tumors by location within the brain or spine. Other brain stem tumors that arm or focal in nature are known to have a quite favorable prognosis in comparison, so looking to get at characteristics of histology or prognosis from non invasive data tumor, location and image ing appearance have historically been analyzed quite extensively. Over the past three decades, certain classifications schemes for brain stem tumors in the pediatric population have evolved with terminology that you see here and for today's discussion will focus on Lee. On this category of masses, the diffuse brain stem tumors, the most relevant dividing line, really remains between masses. That air diffuse on imaging versus those that are well circumscribed. And a discussion of diffuse tumors is essentially a discussion of D ypg diffuse intrinsic Ponting Glioma D. A. P. G is an invasive NIA plasm that tends to originate in the ponds, and it represents 75% approximately of all pediatric brain stem tumors. Even UM, it represents the most aggressive pediatric primary brain brain tumor. And even with the best available treatment, it has a dismal prognosis. Some statistics on prognosis for D A PG include a median overall survival of 8 to 12 months. Ah, one year progression progression free survival of approximately 20%. Ah, mean overall survival at one year of 45% and a mean overall survival of two years. Uh, that's extremely low. What's more is that the change in overall survival over the past three decades has been just about 0%. Some actual actuarial measures for D. I P G include a median age for a new diagnosis around 6 to 7 years and a peak and incidents from between ages 3 to 9 years. Do note that a second peak and incidents occurs in adults at an age of about 34 years, with a very different progression progression free survival on overall survival compared to that of the pediatric population. Approximately five times greater overall D A PG occurs about equally in males and females, so given the limited options for treatment, and the challenging nature of the tumor location. The motivation is long existed to reliably and non invasively. Identified i p. G. In a za consequence of this, the semantic entity typical or classic D. I. P. G. Has arisen and is very important to understand because historically it's had a role as a surrogate for tissue diagnosis. The utility of this framework, the typical or classic nomenclature is it's positive predictive association with histological confirmed the I. P. G. And this association in practice has been well documented in cases with these typical features. So the question then becomes what defines a typical D i. P. G. A typical or classic die PG has a definition that occasionally is controversial, but a reasonable description include certain clinical features. These would include a short, symptomatic course prior presentation, cranial nerve signs, Sarah Beller signs, for example, ataxia certain long track signs that may be present like weakness or hyper reflexive and extra ocular movement disorders. Certain typical or classic radiographic features include a central location of the mass within the ponds where the tumor itself occupies greater than half of the ponds itself. A lack of well defined outer margins hyper intensity on T two Weighted Marie and Hypo Intensity on T one weighted Marie ah lack of significant enhancement There may be enhancement within the tumor, but the enhancing region itself comprises less than 25% of the tumor volume and engulf mint of the basilar artery. Certain features are cited as a typical in certain circumstances, and these could include prominent enhancement, restricted diffusion, cystic components and a prominent exa fitted component. But again, occasionally these air controversial. So how does characterization of a D. I. P. G s either typical or atypical impact the decision for future treatment and the decision to biopsy? So the decision making process for Steri attacking biopsy condemn for between neurosurgeons prior to the general availability of Marie and modern Steri attack. See that we'll talk about in a minute. The rates of morbidity mortality for brain stem biopsy were thought to be near 30% morbidity and 4% mortality. Very high numbers, thes high rates and the ever present prioritization of patient safety led to the reduced availability of tissue for investigating and refining treatment of D. A PG. Over the last three decades, modern estimates of morbidity and mortality from large meta analysis are quite a bit lower. Um, these include a 6.7% transient morbidity, a 0.6% permanent morbidity and a 0.6% mortality. And these Air national statistics, The average rate of non diagnostic brain stem biopsy for presumed D. I. P G has also been estimated, and that's around 3.9%. Therefore, in light of these revised estimates for morbidity mortality and in light of the current state of the field in neurosurgery neuro oncology a reasonable current recommendation for when the biopsy includes offering a biopsy in the setting of an atypical appearing lesion to rule out of pathology that would otherwise dramatically alter treatment strategy. And also offering a biopsy for a typical peering lesion when it serves as the entrance requirement from available clinical trial. The seeming simplicity These criteria for biopsy is tempered by reality in response to a survey with brain stem tumor images and clinical scenarios, Ah, three quarter majority agreement between pediatric neurosurgeons was observed in fewer than half the cases, and a median 5% of pediatric neurosurgeons would choose to biopsy a lesion they themselves designated typical with a range of 1% to 67% quite large, and furthermore, median 18% with a range of 4 to 100% would avoid biopsy of a lesion they themselves called atypical on the survey, let's discuss a little further than the modern role of biopsy data from retrospective reviews of biopsy. Lesions naturally contain selection bias because the lesions, historically with a typical features, were the ones that were biopsied with that in mind. A meta analysis of 18 studies was published with 735 biopsies in all, and they showed that certain pathologies, such as the expected glioma histology, was present in 84% of cases. However, other pathologies including, um, a primitive neuro ectodermal tumor, now Atmar a panda. MoMA. Other tumors infection, inflammatory disease and other neo plastic disease were present in a fairly significant percentage of cases. And remember that these data are best regarded as representing the atypical appearing group of tumors. The data highlights the relevance of biopsy for a typical features. A diagnosis of an embryo, no tumor with multilayered rosettes carries a more rapid dismal prognosis and requires work up, including a full central nervous system imaging consideration of surgical resection and complete cranial spinal radiation. Furthermore, Nani a plastic conditions, for example, acute disseminated encephalomyelitis require cortical steroids, his first line treatment. So you can see that other pathologies, if they're present, would dramatically alter the prognosis and the treatment strategy for lesions. With a typical appearance, biopsy of tissue was historically designated with the standard W H O grading system between two and four. However, the body of literature at the time failed to find a meaningful association between histological grades two through four and the overall survival or the progression free survival of D I. P. G. This was initially puzzling for a substantial period of time, and the lack of association had many theories. Um, it was speculated to derive from sampling error on biopsy. Among other possible reasons, Progress in molecular and Genomic Evaluation of D. P. G has suggested that the clinical behavior is explained by MAWR than just histology alone and substantial meaningful progress in our current understanding of the A. P G was gained in 2012 upon the discovery of the H three K 27 m mutation. Therefore, let's focus on a brief discussion of H three k 27 m. The H three K 27 amputation is a somatic gain of function mutation. Present in more than 80% of D P G. It's a single amino acids substitution that occurs at the 27th amino acid on his stone 3.3 or 3.1 from a polar or charged listen, which is K to a hydrophobic meth inning. As of the 2016 w. H o reclassification, h three k 27 m d. A. P G. Has been designated a specific subset off overall diffuse midline glioma, or H three K 27 m mutated diffuse midline glioma, which is W H O gray four. Regardless of histology, the overall survival of K 27 m d p G is significantly shorter than that of H three Wild Type D, A, P G and the H three K 27. A mutation influences prognosis to a greater extent than age, histological, grade and even treatment. So, speaking of treatment, let's progress to a discussion of therapeutic therapeutic modalities for deep G in the modern era. Biopsy, for example, the biopsies that we performance C h l A. Could be performed using adjuncts to improve surgical safety and accuracy, including three dimensional stereotype axes and robotic neuro navigation. Micro surgical resection is not an advantageous form of therapy for D. P G. Therapeutic Benefit and D A P G has historically been derived from radiation radiation therapy for D. I. P. G's delivered a za fractionated focal dose intensity modulated radiation therapy to a to a region spanning approximately two centimeters around the tumor. Common parameters for radiation therapy include a 1.8 or two gray daily fractions over a course of six weeks, which makes up 30 fractions and as a result of radiation. Symptoms and quality of life do temporarily improved in approximately 80% of patients, and a stabilization or reduction of tumor size occurs in approximately 50%. The overall survival is estimated to increase about three or more months as a result of radiation. But as you can see, this is still very low. Even with radiation, tumor progression occurs on average, 3 to 8 months after therapy and the time from progression. Immortality remains 1 to 4 months. Modifications of the current Radiotherapy regiment have been attempted, including Hypo Fracture Nation or hyper fracture nation, but all without substantial benefit. Improved therapies are dramatically needed for Die Pig. Over 200 clinical trials have been performed using an extensive range and combination of chemo, therapeutics, targeted therapies and other modalities. For example, intra ethical chemotherapy, all without substantial benefit, is well. And as of as of June 2019, there were 28 clinical trials in the United States that were recruiting specifically for D. I. P G. And 13 active studies that were no longer pursuing recruitment. Yeah, promising new options do take advantage of the modern knowledge of the H 3 27 amputation. And these include examples such as his stone diacetyl ace inhibitors such as Pana Been Estado Verena Stat, Bruno Bruno Domain inhibitors or Jumanji Domain DEA, said Elise or dimethyl Ace inhibitors like G s K J four Most clinical trials have that have been reported already in textbooks. For example, targeting of P D. G F R E, G, f, R or veg fr have already shown a lack of significant efficacy. Immunotherapy is also a current important topic of investigation. Inactive clinical trials, including such modalities as vaccine therapies, car T cell therapies, or on politic viruses. R D I. P g laboratory at U. S. C. C H l A and the Saban Research Institute takes advantage of modern knowledge on D. A PG and we're pursuing avenues such as three dimensional cell culture and modeling of the native D. A PG tissue micro environment. We do this through patient derived, multi cell coal cultures as well as human brain derived scaffolds that better reflect the characteristics of the extra cellular matrix and the malignant phenotype. This is moving us towards a high throughput, patient derived micro fluid IQ ass A for drug screening that could dramatically improve therapy in the future. Another avenue that's pursued by our research group, the Nanoscale Neuro Technology Research Group, is Nana part nanoparticle therapies used for D. I. P. G as well as conviction enhanced delivery. Thank you very much for listening to this talk. The information provided here and the work that we do a C H. L. A is a team based effort. There are many colleagues from the hospital staff, the physicians, nursing staff and all of our support staff as well as individuals in our laboratory, which make up an extensive multi disciplinary team that all contribute to improving the overall outcomes and therapy for for Children with D I P G. Thank you very much.